Hat acetylation promoters and uses of compositions thereof in promoting immunogenicity

Abstract

The invention provides processes and compositions for enhancing the immunogenicity of TAP-1 expression-deficient cells by increasing the presentation of MHC Class I surface molecules for detection by cytotoxic T-lymphocyte cells through increased TAP-1 expression, which comprises administering to the TAP-1 expression-deficient cells a TAP-1 expression increasing amount of a bio-acceptable substance that promotes transcription of TAP-1 gene in the cells to cause enhanced MHC Class I surface expression of the cells. The bio-acceptable substance may be a histone H3 deacetylase inhibitor, such as trichostatin A, a transcriptional co-activator having intrinsic histone acetyl transferase activity or a histone acetyl transferase comprising at least one member of the CBP/p300 protein family. The process and compositions increase the immunogenicity of the target cells to enhance their destruction by cytotoxic lymphocytes.

What is claimed is: 
     
         1 . A process of enhancing the immunogenicity of pathological cells and antigen presenting cells by increasing the presentation of MHC Class I surface molecules for detection by cytotoxic T-lymphocyte cells, precursors of cytotoxic T-lymphocyte cells, and memory cytotoxic cells which comprises administering to the cells an effective amount of a bio-acceptable substance that promotes transcription of genes in the cells to cause enhanced MHC Class I surface expression of the cells. 
     
     
         2 . The process of  claim 1 , wherein the genes are selected from the group consisting of TAP-1, TAP-2, LMP-2, tapasin, Beta-2 microglobulin, B7-1, B7-2, CD28, MHC Class I, Erp57, LMP-7, PA28, IRP-I, 2,3,4,5,6,7, CBP, CIITA, RFX5, RFXAP, TNF-alpha, Complement C2, C4, CD80, CD86, human leukocyte antigen (HLA)-DR, HLA-ABC, intracellular adhesion molecule-1 (ICAM-I), Toll-like receptors (1-11), macrophage inflammatory protein-3β/chemokine, motif CC, ligand 19-induced, nuclear factor-{kappa} B, CBP, PCAF and SRC-I, p21, expression of TRAIL (Apo2L, TNFSF10), Statl, interferon alpha, vascular endothelial growth factor, hypoxia-inducible factor 1α and matrix metalloproteinase 9. 
     
     
         3 . The process of  claim 1  wherein the cells are sub-optimal in TAP-1 expression. 
     
     
         4 . The process of  claim 1  wherein the bio-acceptable substance is a histone H3 deacetylase inhibitor. 
     
     
         5 . The process of  claim 4  wherein the histone H3 deacetylase inhibitor is a hydroxamic acid-based histone H3 deacetylase inhibitor. 
     
     
         6 . The process of  claim 4  wherein the histone H3 deacetylase inhibitor is trichostatin A. 
     
     
         7 . The process of  claim 1  wherein the bio-acceptable substance is a transcriptional co-activator having intrinsic histone acetyl transferase activity. 
     
     
         8 . The process of  claim 1  wherein the bio-acceptable substance is a histone acetyl tranferase. 
     
     
         9 . The process of  claim 8  wherein the histone acetyl transferase is selected from the group consisting of CBP/p300 protein family members, p21, Statl, and hypoxia-inducible factor 1α. 
     
     
         10 . The process of  claim 9  wherein the histone acetyl transferase comprises at least one member of the CBP/p300 protein family. 
     
     
         11 . The process of  claim 1  wherein the amount is insufficient to trigger apoptosis. 
     
     
         12 . The process of  claim 1  wherein the administration occurs in vivo. 
     
     
         13 . The process of  claim 1  wherein the administration occurs ex vivo. 
     
     
         14 . The process of  claim 13  wherein the bio-acceptable substance is a histone deacetylase inhibitor, and the substance is administered by an exposure in vitro to the cells at a concentration of not more than 100 ng/ml for not more than 50 hours. 
     
     
         15 . The process of  claim 13 , wherein the bio-acceptable substance is a histone deacetylase inhibitor, and the substance is administered at a daily dose of not more than 0.5 mg/kg. 
     
     
         16 . The process of  claim 13 , wherein the cell is an antigen presenting cell, a dendritic cell, a phagocytic cell, a cell of a monocyte lineage, a cell of a macrophage lineage, a polymorphonuclear cell, a cell of a neutrophil lineage, an endothelial cell, an astrocyte, or a cell infected by a microorganism. 
     
     
         17 . The process of  claim 1  further comprising confirming prior to said administration that the cells are deficient in presentation of MHC Class I surface molecules for detection by cytotoxic T-lymphocyte cells as compared to non-pathological cells. 
     
     
         18 . The process of  claim 1  further comprising confirming prior to said administering that the cells are TAP-I deficient as compared to non-pathological cells. 
     
     
         19 . A pharmaceutical composition for administration to a mammal to enhance MHC Class I surface expression of cells thereof, the composition comprising an amount of bio-acceptable substance that is effective to promote transcription of genes in the MHC Class II or Class I chromosomal region to cause enhanced MHC Class I surface expression of the cells, said amount of bio-acceptable substance being insufficient to trigger apoptosis, and a suitable adjuvant or carrier. 
     
     
         20 . The composition of  claim 19  wherein the bio-acceptable substance is a histone deacetylase inhibitor. 
     
     
         21 . The composition of  claim 19  wherein the bio-acceptable substance is a histone H3 deacetylase inhibitor. 
     
     
         22 . The composition of  claim 20  wherein the histone deacetylase inhibitor is a hydroxamic acid-based histone H3 deacetylase inhibitor. 
     
     
         23 . The composition of  claim 20  wherein the histone deacetylase inhibitor is selected from the group consisting of Tricostatin A, depsipsptide, suberonylanilide hydroxamic acid, amide analogues of Trichostatin A, Trapoxin, hydroxyamic acid analogues of Trapoxin, Scriptaid (6-(1,3-Dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-hexanoic acid hydroxyamide), and Scriptaid analogues. 
     
     
         24 . The composition of  claim 20  wherein the histone deacetylase inhibitor is trichostatin A. 
     
     
         25 . The composition of  claim 19  wherein the bio-acceptable substance is a histone acetyl transferase. 
     
     
         26 . The composition of  claim 19  wherein the bio-acceptable substance is a transcriptional co-activator having intrinsic histone acetyl transferase activity. 
     
     
         27 . The composition of  claim 25  wherein the histone acetyl transferase is selected from the group consisting of CBP/p300 protein family, p21, Statl, and hypoxia-inducible factor 1α. 
     
     
         28 . The composition of  claim 19  further comprising a vaccine formulation. 
     
     
         29 . The use of  claim 19 , further comprising the use of a DNA vaccine, a protein based vaccine, or a vaccine adjuvant. 
     
     
         30 . The composition of  claim 19  wherein the cell is a cancer cell. 
     
     
         31 . The composition of  claim 19  wherein the cell is a cell infected by a microorganism. 
     
     
         32 . The composition of  claim 19  wherein the cell is a cell infected by a virus. 
     
     
         33 . A method of preparing a cell-based vaccine comprising
 obtaining cells from a patient;   treating the cells with a histone deacetylase inhibitor or a histone acetylase promoter; and,   vaccinating a patient with the treated cells.   
     
     
         34 . The method of  claim 33 , wherein the cells are rendered replication-defective prior to the step of vaccinating the patient. 
     
     
         35 . The method of  claim 33 , wherein the cells are irradiated prior to the step of vaccinating the patient to render the cells replication-defective. 
     
     
         36 . A method of screening for a cell treatment regimen that elicits in a cell a histone deacetylase inhibitor activity and does not elicit an apoptosis promoting activity, comprising
 exposing a cell to one or more test compounds at one or more test concentrations; and,   assaying for the level of histone deacetylase activity in the cell and assaying for the level of apoptotic activity in the cell.   
     
     
         37 . The method of  claim 36 , wherein the compounds are selected from the group consisting of Tricostatin A, depsipsptide, suberonylanilide hydroxamic acid, amide analogues of Trichostatin A, Trapoxin, hydroxyamic acid analogues of Trapoxin, Scriptaid (6-(1,3-Dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-hexanoic acid hydroxyamide), and Scriptaid analogues.